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The Pharmaceutical Journal 551

ONE in 5,000 people has Ehlers-Danlos syndrome — at least twicethe number as have sickle cellanaemia, phenylketonuria orhaemophilia A. EDS is a heritabledisorder of collagen, which is amajor component of connectivetissue. Mutations of the genesinvolved in the structure,production and processing ofcollagen underlie the condition.Since connective tissue isabundant throughout the body,EDS can affect the skin,ligaments, muscles, blood vesselsand organs. (see Figure 1 formanifestations)

SubclassificationAlthough symptoms ofhypermobility and skin scarringhave been described for centuries,the first clinical description ofEDS was made in 1892 and thecondition was later named aftertwo dermatologists, Edvard Ehlersand Henri-Alexandre Danlos. In1998 the major subtypes of EDSwere classified according to theirclinical features and geneticfindings.

The three most commonsubtypes, described in Panel 1,are:

•Classic

•Hypermobility

•Vascular

Ever heard of Ehlers-Danlos syndrome?May is Ehlers-Danlos syndrome awareness month. Despite being as prevalent as cysticfibrosis, EDS is not as well known among healthcare professionals. Learn more about it hereSUSAN ALLEN FREELANCE WRITER AND LECTURER AT THE LEICESTER SCHOOL OF PHARMACY

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• Ehlers-Danlos syndrome is agenetic disease that often goesundiagnosed or ismisdiagnosed, despite causingsignificant morbidity.

• Pharmacists can play a part inrecognising and referring thosewith symptoms.

• Pharmacists can also advise onmedicines to manage specificsymptoms while being mindfulof side-effects and potentialinteractions

KEY POINTS

1 Would you recognisesymptoms of Ehlers-Danlossyndrome? (EDS)

2 What sorts of medicines mighta person with EDS take?

3 Do you feel prepared to advisea patient with EDS?

Before reading on, think abouthow this article may help you todo your job better.

REFLECT

Clinical diagnosis is based onthe presence or history of majorand minor diagnostic criteriaalongside family history. Thevague and insidious onset ofsome symptoms means patientsoften go undiagnosed or aremisdiagnosed for years.

All EDS subtypes tend to sharecommon characteristics of:

• Soft skin

• Easy bruising

• Joint laxity

A genetic defect has beenidentified for all subtypes apartfrom hypermobility type(EDS-HT); this is the mostcommon subtype and the focusof this article.

The classic and hypermobilitysubtypes together make up 90%of all EDS cases and men andwomen of all racial and ethnicbackgrounds can be affected.Life expectancy at birth forpeople with the classic andhypermobility subtypes is usuallyas for the general populationalthough considerable morbidityand disability often results,particularly with EDS-HT.

Vascular EDS is thought toaccount for around 4% of EDScases and is life-threatening.Vasculature or organ rupture is amajor cause of early death at amedian age of 48 years.Pregnancy is particularlydangerous in vascular EDS.

Diagnosis Joint hypermobility is oftenthe first clear manifestation of

A person with Ehlers-Danlos syndrome (COURTESY OF EHLOS-DANLOS SUPPORT UK)

EDS-HT in childhood.Diagnosis of EDS-HT is madeon the basis of an individualshowing all three major diagnosticcriteria accompanied by minordiagnostic criteria listed in Panel2.

There is overlap between EDS-HT and a condition knownas joint hypermobility syndrome(JHS) and discrepancy amongclinicians as to the relationshipbetween them. EDS-HT tends tobe viewed as more serious andthe associated hypermobilityoccurs alongside other significantsigns and symptoms which arethe manifestations of faultycollagen.

Management of symptomsFour potentially troublesomesymptoms that can cause apatient with EDS-HT to presentat the pharmacy are:

• Joint laxity

• Pain

• Gastric problems

• Dysautonomia

EDS-HT is a spectrumdisorder — not all patients willsuffer all of these symptoms andsome will have additionalsymptoms.

Joint laxityThe term “joint hypermobility” isused when the range of movementof the joint goes beyond itsnormal range. Hypermobility ismore common in females and

those of Asian, African orCaribbean origin.

Reflect

Act

Evaluate Plan

About 10% of the generalpopulation have a degree ofhypermobility and may bedescribed as “flexible” or “doublejointed”. This can beadvantageous, helping themexcel at, for example, ballet orgymnastics. However, insomeone with EDS-HT (or JHS)the weakness and laxity ofligaments and tendonssupporting the joints results infrequent dislocations orsubluxations (partial dislocation)and predisposes a person tosprains, tendonitis and bursitis.Simple movements (such aschanging direction when walkingor turning over in bed) or lightknocks can cause jointdisplacement. This impairs aperson’s ability to carry out day-to-day activities such as walking,dressing and writing.

The EDS individual canusually return the dislocated jointto its natural position themselves,but the trauma of dislocationcauses inflammation and pain,which can last for days, and avicious circle of events that makeit difficult to recover and regainmuscle and joint strength (seeFigure 2).

Commonly affected joints arethe knee, shoulder, hip and jaw.Physiotherapy and occupationaltherapy is vital in EDS andpatients require personalisedexercise programmes tostrengthen muscles and jointsand remain mobile. Non-stressactivities, such as swimming, areparticularly beneficial. Weightbearing and contact activitiesshould be avoided.

Despite physiotherapy, someindividuals need to wear bracesto stabilise joints or use crutchesor a wheelchair.

PainJoint hypermobility in EDS-HTtends to be followed bydislocations and then articular,muscular and back pain. Thesecommonly begin during thesecond decade. Joint stiffness andosteoarthritis occur later, but atan earlier age than in the generalpopulation.

The chronic pain associatedwith EDS-HT may bemyofascial (muscular pain,tenderness or spasm),neuropathic orarthralgic/osteoarthritic inorigin.2 Back pain, abdominalpain and headache (includingmigraine) are also common.Chronic pain can be difficult tomanage and helping patientsdevelop relaxation and copingstrategies is important alongsidepharmacological measures.

There are no standardisedguidelines for the assessment andtreatment of pain in EDS-HTbut it is important to manage it:chronic pain is debilitating andcan have severe psychologicaleffects. In addition, those withEDS have an increased incidenceof anxiety and depressioncompared with the generalpopulation.

Drugs recommended by theNational Institute for Health andCare Excellence forosteoarthritis3 and fibromyalgiaare good starting points.However, use of these drugs in

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Ask theexpert

The author will be availableto answer questions on thistopic until 9 June 2014

www.pjonline.com/expertFigure 1: Could it be EDS? (COURTESY OF EHLERS-DANLOS SUPPORT UK)

EDS presents challenges becausetheir side effects may exacerbateother EDS symptoms.

Paracetamol Patients with EDSroutinely use Paracetamol forpain relief. NICE and theMedicines and Healthcareproducts Regulatory Agency is

Hypermobility type

• Joint laxity of largeand small joints(dislocation andsubluxation ofshoulder, patella,jaw, hip and fingersis common andfrequent)

• Chronic joint paindevelops

• Soft, smooth skin,moderate skinelasticity, noscarring, easybruising

• Blue sclera• Fatigue and sleepdisturbances

Other features can include:

• Gastrointestinal dysfunction (eg, delayed gastricemptying, constipation, irritable bowel syndrome)

• Autonomic dysfunction, including posturalorthostatic tachycardia syndrome (POTS)

• Irregular menstrual cycle (and worseningsymptoms around menstruation)

• Urinary dysfunction and incontinence• Other skin manifestations (eg, keratosis pilaris [tinyred “goose bump” type rash seen on the upperarms or thighs more commonly in EDS than in thegeneral population], piezogenic papules [fatherniations through defects in the dermis],petechiae [pinpoint red/purple haemorrhages])

Classic type

• Joint laxity• Velvety, hyper-elastic, fragile skin that splits easily,heals slowly and leads to atrophic scars; easybruising

Other features can include:

• Other skin features (piezogenic papules on sides offeet and molluscoid pseudotumors [cystlikenodules on bony prominences])

• Blue sclerae•Hernias and prolapses (uterine, anal)• ScoliosisVascular type

• Spontaneous rupture of medium or large arteriesat any age from mid-teens onwards

• Skin shows only mild hyperextensibility but isfragile. It is also thin, appearing translucent(showing underlying veins and capillaries)especially on the chest and abdomen

• Easy bruising• Scars are numerous• Perforation of hollow organs such as bowel oruterus

Other features can include:

• Distinctive facial appearance (prominent eyes, thinface, lips and nose, lobeless ears)

• Small fingers and toes, which may be hypermobile,but no large joint hypermobility

• Early onset varicose veins• Premature aging of the skin on the hands and feet• Bleeding or receding gums

Keratosis pilaris can be a feature ofEDS-HT (CID/ISM/SPL)

PANEL 1: COMMON EDS SUBTYPES AND THEIR SYMPTOMS1,2

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The Pharmaceutical Journal 553

this in EDS do not appear tohave been documented.

Antidepressants and anti-seizuremedicines Low-dose tricyclicantidepressants, (eg,amitriptyline at night) can helpwith neuropathic pain and havevalue in the sleep disturbancescommonly experienced by EDSpatients. Side effects of posturalhypotension, tachycardia anddizziness may exacerbatesymptoms associated withdysautonomia and posturalorthostatic tachycardiasyndrome (POTS) and patientsshould be counselled accordingly.Further, the constipatingtendency of tricyclics maycompound constipating sideeffects of concurrent opioidanalgesics and the tendencytowards constipation some EDSpatients.

Other antidepressantmedication (eg, venlafaxine andduloxetine) and anti-seizuremedication (eg, gabapentin) arealso sometimes used to manageneuropathic pain. They should beused with caution where otherdrugs with serotonergic potentialare also being taken because ofthe risk of serotonin syndrome.

Opioids Weak opioids, such ascodeine, combined withparacetamol or alone, aresometimes used for pain.Tramadol is also used formoderate to severe pain that isunresponsive to other analgesics.Consideration needs to be givento the side effects of dizziness,drowsiness, nausea, palpitations,postural hypotension andconstipation, which are alsosymptoms associated with EDS.

Muscle relaxants The skeletalmuscle relaxant baclofen actscentrally and is occasionally usedfor muscle related pain thoughtto have a neurologicalcomponent. There are a numberof cautions related to its use.4

Doses should be carefully titratedto reduce the likelihood of sideeffects and the medicine shouldbe withdrawn carefully bygradual dose reduction over oneto two weeks.

Gastric problemsCollagen abnormalities in theextracellular matrix surroundingthe gastrointestinal tract can alterthe way it stretches and affect guttransit time. In addition,autonomic dysfunction can

aggravate symptoms.Gastrointestinal symptoms suchas dyspepsia and reflux, nausea,dysphagia, abdominal pain andaltered bowel habit are commonfor patients with EDS.

Reflux and dyspepsia areusually managed with protonpump inhibitors (eg,lansoprazole). However, patientscan still have symptoms despitemaximum doses and H2-receptorantagonists (eg, ranitidine) andantacids or alginates. Patientstaking PPIs long term (ie, formore than one year) and in highdoses have an increased risk ofbone fracture5 although therelationship may not be causal.EDS patients are already at riskof osteoporosis and should beadvised to maintain an adequatecalcium intake or takesupplements where necessary.Calcium and vitamin Dsupplements may be usefulparticularly when PPIs are taken,patients are inactive, theirexposure to sun is limited ordietary intake is lacking. Further,hypomagnesaemia may alsoresult from PPI treatment(usually after a year butsometimes after just threemonths).

Prokinetic agents can help withsymptoms of nausea and earlysatiety due to delayed gastricemptying. Domperidoneincreases gastric emptying andmotility; new restrictions limit itto the relief of nausea andvomiting, and it should nolonger be used for heartburn,bloating or relief of stomachdiscomfort.6 Metoclopramide hasalso been used, but newguidelines now further restrictthis due to unacceptableneurological risks.4

Concurrent opioid analgesicscan antagonise the effects ofthese drugs.

Symptoms akin to irritablebowel syndrome (IBS) arecommon in EDS. Patients canexperience abdominaldiscomfort, bloating,constipation or diarrhoea. As inIBS, exclusion diets can be ofbenefit, including avoidinggluten, lactose and highFODMAP foods. FODMAPs(fermentable oligosaccharides,disaccharides, monosaccharidesand polyols) are short-chaincarbohydrates that are poorlyabsorbed from the gut andrapidly fermented by gutbacteria, producing gas andbloating. A low FODMAP diet is

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Major diagnostic criteria

• Joint hypermobility (score ≥5on Beighton scale*)

• Soft skin with normal or onlyslightly increasedextensibility

• Absence of skin fragility orother skin or soft tissueabnormalities such as poorhealing, hernias, translucentskin, atrophic scars

Minor diagnostic criteria

• Positive family history

• Recurrent joint dislocationsor subluxations

• Chronic joint, limb or backpain

• Easy bruising

• Functional bowel disorders(reflux, irritable bowelsyndrome)

• Autonomically mediatedhypotension or posturalorthostatic tachycardiasyndrome (POTS)

•High narrow palate

• Dental crowding

* Beighton score (out of a maximumscore of 9 points) to assess degree ofhypermobility by:

Bending small finger back more than90 degrees (1 point per little finger)

Bending thumbs to touch forearm (1 point per thumb)

Hyperextending elbows and kneesbeyond the straight line (1 point foreach joint [maximum 4 points])

Putting hands flat on the floor withoutbending knees (1 point)

PANEL 2: DIAGNOSISOF EDS-HT2

Figure 2: Joint trauma and laxity cycle

conducting a review into thesafety of over-the-counteranalgesics following someevidence relating to thecardiovascular, gastrointestinaland renal side effects ofparacetamol. The results will berelevant because EDS patientscommonly take pain-relievingmedicines for many years, oftenstarting in young adulthood.

Topical NSAIDs Topical non-steroidal anti-inflammatorydrugs (eg, ibuprofen gel) areadvocated by NICE ahead of oralNSAIDs, cyclo-oxygenase-2inhibitors and opioids for painmanagement in osteoarthritisassociated with the knee andhand joints.3 After topicalapplication, therapeutic druglevels can be detected in synovialfluid. Plasma concentrations,however, are 15% of those seenafter oral NSAIDs, so it can beexpected that side effects arereduced by topical use. This isrelevant in EDS because gastricsymptoms associated with thecondition are frequentlytroublesome.

Topical capsaicin Topicalcapsaicin is an adjunct fortreating pain in osteoarthritis forhand and knee joints.3 It is alsoused in EDS, although there isno evidence to support itsefficacy. It may need to beapplied for one to two weeksbefore any effect is experienced.

Oral NSAIDs Oral NSAIDS (eg,ibuprofen or naproxen) andCOX-2 inhibitors (eg, celecoxib)are commonly prescribed tomanage acute symptoms. NICEadvocates using the lowestpossible dose for the shortestperiod of time and co-prescribing a proton pumpinhibitor to protect againstgastric side effects. Patientsshould be advised to report anyincrease in gastric symptoms.

There is comment in the BNFthat patients with connectivetissue disorders may besusceptible to aseptic meningitis,when taking NSAIDs. Thisderives from a report of a patientwith systemic lupuserythematosus andmanufacturers do not have anyevidence relating to EDS.NSAIDs have been shown tohave both a positive and negativeeffect on collagen synthesis andcontent of tendons, ligamentsand cartilage. The implications of

Dislocation

Trauma andinflammation

Pain andimmobility

Increasedjoint laxity

Musclewasting

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one of avoidance (or limitation)and excludes, for example, somedairy products, wheat andcertain fruits and vegetables thatare high in fructose or polyols,such as apples, cherries,mushrooms.7

Dietary supplements Takingvitamin and mineral supplementsin addition to calcium andvitamin D to help symptoms andavoid long-term complications ofEDS is sometimes proposed.8

Vitamin C is involved in collagensynthesis and repair and is oftenrecommended. Doses higherthan 500mg are probablyexcreted and so offer noadditional benefit. Magnesiumdeficiency can affect calcium andvitamin D levels and it isinvolved in collagen synthesis.Magnesium supplementation hasbeen proposed in EDS asdeficiency is thought to becommon in the generalpopulation and in patients takingPPIs long term.9

There is some evidence thatcertain probiotics can bebeneficial in IBS in reducingbloating. With all these dietarysupplements, specific studiesrelating to EDS are lacking.

DysautonomiaPeople with EDS-HT canexperience dysautonomia andautonomic dysfunction. Theseaffect involuntary functionsrelating to heart rate, breathing,digestion, balance andtemperature regulation, andcause symptoms that are difficultto recognise and diagnosebecause of vague or lackingoutward signs. Misdiagnoses ofanxiety disorders can add to thestresses that sufferers face.

One of the manifestations ofautonomic dysfunction isorthostatic intolerance andPOTS. The autonomic nervoussystem is unable to adapt tochanges in body position, forexample from lying down tositting or standing. POTS isdiagnosed by either an increasein pulse of more than 30beats/min, or greater than 120beats/min, 12 minutes afterstanding from being supine,without any further exertionother than that required tochange position.

When an individual with normalautonomic function and no jointhypermobility syndrome standsfrom lying or sitting there is a briefpooling of blood in the lower parts

Reading is only one way toundertake CPD and the regulatorwill expect to see variousapproaches in a pharmacist’sCPD record.

1 Help increase awareness ofEhlers-Danlos syndrome bysharing your learning withothers. Leaflets are availablefrom www.ehlers-danlos.org

2 Find out more about thepatient experience of Ehlers-Danlos syndrome — a numberof videos are available onYouTube

3 Be aware of the type ofsymptoms described in thisarticle in your teenage/youngadult population. Mightsomeone with these symptomshave undiagnosed EDS?

Consider making this activity oneof your nine CPD entries this year.

Learning &developmentUnless stated otherwise,Learning & developmentmaterial is commissionedby The Journal and is notpeer-reviewed

PRACTICE POINTSof the body, which, in turn,reduces blood pressure andcerebral blood flow. This results insympathetic nervous systemactivation to compensate, andcauses an increase in heart rate,force of contraction andvasoconstriction of blood vessels.In an EDS-HT individual withPOTS, standing causes thepooling of blood in the lower body,heart rate is increased, but theblood vessels do not adjust in thesame way. As a consequence theblood pressure can remain low, theheart rate remains fast anddizziness, confusion and faintingresult. Excess adrenaline can alsoresult as the body attempts tocompensate, producing additionalsymptoms (eg, tremor, feelings offear, flushing). These symptoms ofdysautonomia can be as disablingas the joint laxity.

The strategy for managingsymptoms starts with non-pharmacological measures andthen a number of drugtreatments can be tried. Non-pharmacological measuresinclude:

•Maintaining adequatehydration by increasing fluidintake (isotonic drinks can behelpful) and salt consumption inthe absence of contraindications

• Eating small frequent meals todivert less blood volume to theintestine for digestion

•Avoidance of alcohol and itsvasodilating and dehydratingeffects

•Tilting the head of the bed withbed raisers or bricks to an angleof around 30 degrees (may alsohelp with night-time reflux)

•Wearing compression hosiery(ideally full length) to givesupport to lower limb vesselsand reduce the venous pooling

•Low resistance exercise to suitsthe individual is also beneficial

No drugs are currently licensedfor managing orthostatichypotension and POTS in theUK, but the following medicinesare sometimes used:

•Fludrocortisone wherehypovolaemia is a problem, toencourage salt and waterretention and aidvasoconstriction. Doses shouldbe as low as possible to avoidadrenal suppression. Note alsothe tendency to increase risk ofgastric bleeding and ulcerationwhen given with NSAIDs andto cause calcium loss.

• Low doses of beta-blockers,(eg, labetolol, propranolol) aresometimes used to controltachycardia where hypotensionis not a factor.10 They are usefulwhere hyperadrenergicsymptoms are troublesome.

• Ivabradine is used to controltachycardia by its action on thesinus node and it improvesdiastolic filling. It has advantageover betablockers since it doesnot have their vasodilatingeffects.

•The parasympathomimeticagent pyridostigmine has beenused with some benefit in POTSto restrain the heart rate rise onstanding. It has also been shownto increase intestinal motilitywhich may have additionalbenefits to some EDS patients.

•The alpha agonist midodrine(unlicensed in the UK) hasbeen used, where there is nohypertension, with somesuccess in maintaining bloodpressure on standing by causingvasoconstriction. Side effectsinclude tingling and goosebumps and the more severesupine hypertension.11

• Selective serotonin reuptakeinhibitors and selectivenoradrenaline reuptakeinhibitors, eg, sertraline andvenlafaxine, are sometimesused because serotonin isimplicated in autonomiccontrol of blood pressure. Theyhave been shown to beespecially useful where syncopeis a significant symptom andalso in treating chest painassociated with POTS.

Pharmacist’s rolePharmacists can play a key rolein recognising EDS symptomsand referring those with signs ofEDS who may present in thepharmacy with queries aboutjoint dislocations, gastro-intestinal problems, centralnervous system symptoms,fatigue, bruising or other skinsymptoms. In addition, they canmake a difference byunderstanding diagnosed EDSpatients and supporting andadvising on medication andcomplementary measures.

Pharmacists can also signpostpatients to support groups suchas Ehlers-Danlos Support UK(www.ehlers-danlos.org) and theHypermobility SyndromesAssociation (hypermobility.org).

References available online.http://bit.ly/1ljSg4J